PROJECT SUMMARY Tuberculosis (TB) remains a leading global health problem, aggravated by HIV co-infections and the emergence of drug-resistant strains of Mycobacterium tuberculosis (M.tb), with diminishing treatment options. This challenge has prompted the quest for novel therapies that aim to shorten the duration of treatment and improve clinical outcomes. Granulomas represent a pathological hallmark of TB. They are comprised of host immune cells that serve not only to contain the invading pathogen, but to also allow for pathogen persistence and ultimate reactivation of dormant infection. Adjunctive host-directed therapies (HDTs) that seek to limit inflammation and lung pathological damage, and to potentiate the host protective components against M.tb infection have emerged an attractive avenue of intervention against both drug-sensitive and drug-resistant forms of the disease, and they critically warrant further exploration. Recent studies have shown that myeloid-derived suppressor cells (MDSCs), which have been shown to contribute to immunosuppression within tumor microenvironments, also accumulate within TB granulomas and contribute to disease fatality. We hypothesize that by reducing the accumulation of MDSCs that provide niches for bacterial persistence and mediate immune suppression of effector responses, and by blocking the effects of pro-inflammatory DAMP molecules S100A8/A9 which promote accumulation of MDSCs and other myeloid cells, disease progression could be impeded and infection could be eliminated. Here we propose to evaluate the efficacies of tasquinimod and paquinimod, quinoline-3-carboxamide analogues (Q compounds) that target MDSCs and S100 proteins, individually and as adjunctive therapies in combination with standard antimicrobial agents, in reducing TB pathology using mouse models. We also propose to determine whether S100A9 levels in serum serve as a valuable biomarker for the evaluation of response to first and second- line anti-TB therapy.